Methods of providing therapeutic effects using cyclosporin components

ABSTRACT

Methods of treating an eye of a human or animal include administering to an eye of a human or animal a composition in the form of an emulsion including water, a hydrophobic component and a cyclosporin component in a therapeutically effective amount of less than 0.1% by weight of the composition. The weight ratio of the cyclosporin component to the hydrophobic component is less than 0.8.

RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.10/927,857, filed Aug. 27, 2004, which claimed the benefit of U.S.Provisional Application No. 60/503,137 filed Sep. 15, 2003, which isincorporated in its entirety herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates to methods of providing desiredtherapeutic effects to humans or animals using compositions includingcyclosporin components. More particularly, the invention relates tomethods including administering to an eye of a human or animal atherapeutically effective amount of a cyclosporin component to provide adesired therapeutic effect, preferably a desired ophthalmic or oculartherapeutic effect.

The use of cyclosporin-A and cyclosporin A derivatives to treatophthalmic conditions has been the subject of various patents, forexample Ding et al U.S. Pat. No. 5,474,979; Garst U.S. Pat. No.6,254,860; and Garst U.S. Pat. No. 6,350,442, this disclosure of each ofwhich is incorporated in its entirely herein by reference. In addition,cyclosporin A compositions used in treating ophthalmic conditions is thesubject of a number of publications. Such publications include, forexample, “Blood concentrations of cyclosporin a during long-termtreatment with cyclosporin a ophthalmic emulsions in patients withmoderate to severe dry eye disease,” Small et al, J Ocul Pharmacol Ther,2002 October, 18(5):411-8; “Distribution of cyclosporin A in oculartissues after topical administration to albino rabbits and beagle dogs,”Acheampong et al, Curr Eye Res, 1999 February, 18(2):91-103b;“Cyclosporine distribution into the conjunctiva, cornea, lacrimal gland,and systemic blood following topical dosing of cyclosporine to rabbit,dog, and human eyes,” Acheampong et al, Adv Exp Med Biol, 1998,438:1001-4; “Preclinical safety studies of cyclosporine ophthalmicemulsion,” Angelov et al, Adv Exp Med Biol, 1998, 438:991-5;“Cyclosporin & Emulsion & Eye,” Stevenson et al, Ophthalmology, 2000May, 107(5):967-74; and “Two multicenter, randomized studies of theefficacy and safety of cyclosporine ophthalmic emulsion in moderate tosevere dry eye disease. CsA Phase 3 Study Group,” Sall et al,Ophthalmology, 2000 April, 107(4):631-9. Each of these publications isincorporated in its entirety herein by reference. In addition,cyclosporin A-containing oil-in-water emulsions have been clinicallytested, under conditions of confidentiality, since the mid 1990's inorder to obtain U.S. Food and Drug Administration (FDA) regulatoryapproval.

Examples of useful cyclosporin A-containing emulsions are set out inDing et al U.S. Pat. No. 5,474,979. Example 1 of this patent shows aseries of emulsions in which the ratio of cyclosporin A to castor oil ineach of these compositions was 0.08 or greater, except for CompositionB, which included 0.2% by weight cyclosporin A and 5% by weight castoroil. The Ding et al patent placed no significance in Composition Brelative to Compositions A, C and D of Example 1.

Over time, it has become apparent that cyclosporin A emulsions forophthalmic use preferably have less than 0.2% by weight of cyclosporinA. With cyclosporin A concentrations less than 0.2%, the amount ofcastor oil employed has been reduced since one of the functions of thecastor oil is to solubilize the cyclosporin A. Thus, if reduced amountsof cyclosporin are employed, reduced amounts of castor oil are needed toprovide effective solubilization of cyclosporin A.

There continues to be a need for providing enhanced methods of treatingophthalmic or ocular conditions with cyclosporin-containing emulsions.

SUMMARY OF THE INVENTION

New methods of treating a human or animal using cyclosporincomponent-containing emulsions have been discovered. Such methodsprovide substantial overall efficacy in providing desired therapeuticeffects. In addition, other important benefits are obtained employingthe present methods. For example, patient safety is enhanced. Inparticular, the present methods provide for reduced risks of sideeffects and/or drug interactions. Prescribing physicians advantageouslyhave increased flexibility in prescribing such methods and thecompositions useful in such methods, for example, because of the reducedrisks of harmful side effects and/or drug interactions. The presentmethods can be easily practiced. In short, the present methods providesubstantial and acceptable overall efficacy, together with otheradvantages, such as increased safety and/or flexibility.

In one aspect of the present invention, the present methods compriseadministering to an eye of a human or animal a composition in the formof an emulsion comprising water, a hydrophobic component and acyclosporin component in a therapeutically effective amount of less than0.1% by weight of the composition. The weight ratio of the cyclosporincomponent to the hydrophobic component is less than 0.08.

It has been found that the relatively increased amounts of hydrophobiccomponent together with relatively reduced, yet therapeuticallyeffective, amounts of cyclosporin component provide substantial andadvantageous benefits. For example, the overall efficacy of the presentcompositions, for example in treating dry eye disease, is substantiallyequal to an identical composition in which the cyclosporin component ispresent in an amount of 0.1% by weight. Further, a relatively highconcentration of hydrophobic component is believed to provide for a morequick or rapid breaking down or resolving of the emulsion in the eye,which reduces vision distortion which may be caused by the presence ofthe emulsion in the eye and/or facilitates the therapeutic effectivenessof the composition. Additionally, and importantly, using reduced amountsof the active cyclosporin component mitigates against undesirable sideeffects and/or potential drug interactions.

In short, the present invention provides at least one advantageousbenefit, and preferably a plurality of advantageous benefits.

The present methods are useful in treating any suitable condition whichis therapeutically sensitive to or treatable with cyclosporincomponents. Such conditions preferably are ophthalmic or ocularconditions, that is relating to or having to do with one or more partsof an eye of a human or animal. Included among such conditions are,without limitation, dry eye syndrome, phacoanaphylactic endophthalmitis,uveitis, vernal conjunctivitis, atopic kerapoconjunctivitis, cornealgraft rejection and the like conditions. The present invention isparticularly effective in treating dry eye syndrome.

Employing reduced concentrations of cyclosporin component, as in thepresent invention, is advantageously effective to provide the blood ofthe human or animal under treatment with reduced concentrations ofcyclosporin component, preferably with substantially no detectableconcentration of the cyclosporin component. The cyclosporin componentconcentration of blood can be advantageously measured using a validatedliquid chromatography/mass spectrometry-mass spectrometry (VLC/MS-MS)analytical method, such as described elsewhere herein.

In one embodiment, in the present methods the blood of the human oranimal has concentrations of clyclosporin component of 0.1 ng/ml orless.

Any suitable cyclosporin component effective in the present methods maybe used.

Cyclosporins are a group of nonpolar cyclic oligopeptides with knownimmunosuppressant activity. Cyclosporin A, along with several otherminor metabolites, cyclosporin B through I, have been identified. Inaddition, a number of synthetic analogs have been prepared.

In general, commercially available cyclosporins may contain a mixture ofseveral individual cyclosporins which all share a cyclic peptidestructure consisting of eleven amino acid residues with a totalmolecular weight of about 1,200, but with different substituents orconfigurations of some of the amino acids.

The term “cyclosporin component” as used herein is intended to includeany individual member of the cyclosporin group and derivatives thereof,as well as mixtures of two or more individual cyclosporins andderivatives thereof.

Particularly preferred cyclosporin components include, withoutlimitation, cyclosporin A, derivatives of cyclosporin A and the like andmixtures thereof. Cyclosporin A is an especially useful cyclosporincomponent.

Any suitable hydrophobic component may be employed in the presentinvention. Advantageously, the cyclosporin component is solubilized inthe hydrophobic component. The hydrophobic component may be consideredas comprising a discontinuous phase in the presently useful cyclosporincomponent-containing emulsions.

The hydrophobic component preferably is present in the emulsioncompositions in an amount greater than about 0.625% by weight. Forexample, the hydrophobic component may be present in an amount of up toabout 1.0% by weight or about 1.5% by weight or more of the composition.

Preferably, the hydrophobic component comprises one or more oilymaterials. Examples of useful oil materials include, without limitation,vegetable oils, animal oils, mineral oils, synthetic oils and the likeand mixtures thereof. In a very useful embodiment, the hydrophobiccomponent comprises one or more higher fatty acid glycerides. Excellentresults are obtained when the hydrophobic component comprises castoroil.

The presently useful compositions may include one or more othercomponents in amounts effective to facilitate the usefulness andeffectiveness of the compositions. Examples of such other componentsinclude, without limitation, emulsifier components, tonicity components,polyelectrolyte components, surfactant components, viscosity inducingcomponents, acids and/or bases to adjust the pH of the composition,buffer components, preservative components and the like. Components maybe employed which are effective to perform two or more functions in thepresently useful compositions. For example, components which areeffective as both emulsifiers and surfactants may be employed, and/orcomponents which are effective as both polyelectrolyte components andviscosity inducing components may be employed. The specific compositionchosen for use in the present invention advantageously is selectedtaking into account various factors present in the specific applicationat hand, for example, the desired therapeutic effect to be achieved, thedesired properties of the compositions to be employed, the sensitivitiesof the human or animal to whom the composition is to be administered,and the like factors.

The presently useful compositions advantageously are ophthalmicallyacceptable. A composition, component or material is ophthalmicallyacceptable when it is compatible with ocular tissue, that is, it doesnot cause significant or undue detrimental effects when brought intocontact with ocular tissues.

Such compositions have pH's within the physiological range of about 6 toabout 10, preferably in a range of about 7.0 to about 8.0 and morepreferably in a range of about 7.2 to about 7.6.

The present methods preferably provide for an administering stepcomprising topically administering the presently useful compositions tothe eye or eyes of a human or animal.

Each and every feature described herein, and each and every combinationof two or more of such features, is included within the scope of thepresent invention provided that the features included in such acombination are not mutually inconsistent.

These and other aspects and advantages of the present invention areapparent in the following detailed description, example and claims.

DETAILED DESCRIPTION

The present methods are effective for treating an eye of a human oranimal. Such methods, in general, comprise administering, preferablytopically administering, to an eye of a human or animal a cyclosporincomponent-containing emulsion. The emulsion contains water, for exampleU.S. pure water, a hydrophobic component and a cyclosporin component ina therapeutically effective amount of less than 0.1% by weight of theemulsion. In addition, beneficial results have been found when theweight ratio of the cyclosporin component to the hydrophobic componentis less than 0.08.

As noted above, the present administering step preferably includestopically administering the emulsion to the eye of a patient of a humanor animal. Such administering may involve a single use of the presentlyuseful compositions, or repeated or periodic use of such compositions,for example, as required or desired to achieve the therapeutic effect tobe obtained. The topical administration of the presently usefulcomposition may involve providing the composition in the form of eyedrops or similar form or other form so as to facilitate such topicaladministration.

The present methods have been found to be very effective in providingthe desired therapeutic effect or effects while, at the same time,substantially reducing, or even substantially eliminating, side effectswhich may result from the presence of the cyclosporin component in theblood of the human or animal being treated, and eye irritation which, inthe past, has been caused by the presence of certain components in priorart cyclosporin-containing emulsions. Also, the use of the presentcompositions which include reduced amounts of the cyclosporin componentsallow for more frequent administration of the present compositions toachieve the desired therapeutic effect or effects without substantiallyincreasing the risk of side effects and/or eye irritation.

The present methods are useful in treating any condition which istherapeutically sensitive to or treatable with cyclosporin components.Such conditions preferably are ophthalmic or ocular conditions, that isrelating to or having to do with one or more parts of an eye of a humanor animal. Included among such conditions are, without limitation, dryeye syndrome, phacoanaphylactic endophthalmitis, uveitis, vernalconjunctivitis, atopic kerapoconjunctivitis, corneal graft rejection andthe like conditions. The present invention is particularly effective intreating dry eye syndrome.

The frequency of administration and the amount of the presently usefulcomposition to use during each administration varies depending upon thetherapeutic effect to be obtained, the severity of the condition beingtreated and the like factors. The presently useful compositions aredesigned to allow the prescribing physician substantial flexibility intreating various ocular conditions to achieve the desired therapeuticeffect or effects with reduced risk of side effects and/or eyeirritation. Such administration may occur on an as needed basis, forexample, in treating or managing dry eye syndrome, on a one time basisor on a repeated or periodic basis once, twice, thrice or more timesdaily depending on the needs of the human or animal being treated andother factors involved in the application at hand.

One of the important advantages of the present invention is the reducedconcentration of the cyclosporin component in the blood of the human oranimal as a result of administering the present composition as describedherein. One very useful embodiment of the present administering stepprovides no substantial detectable concentration of cyclosporincomponent in the blood of the human or animal. Cyclosporin componentconcentration in blood preferably is determined using a liquidchromatography-mass spectroscopy-mass spectroscopy (LC-MS/MS), whichtest has a cyclosporin component detection limit of 0.1 ng/ml.Cyclosporin component concentrations below or less than 0.1 ng/ml aretherefore considered substantially undetectable.

The LC-MS/MS test is advantageously run as follows.

One ml of blood is acidified with 0.2 ml of 0.1 N HCl solution, thenextracted with 5 ml of methyl t-butyl ether. After separation from theacidified aqueous layer, the organic phase is neutralized with 2 ml of0.1 N NaOH, evaporated, reconstituted in a water/acetonitrile-basedmobil phase, and injected onto a 2.1×50 mm, 3 μm pore size C-8 reversephase high pressure liquid chromatography (HPLC) column (KeystoneScientific, Bellefonte, Pa.). Compounds are gradient-eluted at 0.2mL/min and detected using an API III triple quadrupole mass spectrometerwith a turbo-ionspray source (PE-Sciex, Concord, Ontario, Canada).Molecular reaction monitoring enhances the sensitivity and selectivityof this assay. Protonated molecules for the analyte and an internalstandard are collisionally dissociated and product ions at m/z 425 aremonitored for the analyte and the internal standard. Under theseconditions, cyclosporin A and the internal standard cyclosporin G elutewith retention times of about 3.8 minutes. The lower limit ofquantitation is 0.1 ng/mL, at which concentration the coefficient ofvariation and deviation from nominal concentration is <15%.

As noted previously, any suitable cyclosporin component effective in thepresent methods may be employed. Very useful cyclosporin componentsinclude, without limitation, cyclosporin A, derivatives of cyclosporin Aand the like and mixtures thereof.

The chemical structure for cyclosporin A is represented by Formula 1

As used herein the term “derivatives” of a cyclosporin-refer tocompounds having structures sufficiently similar to the cyclosporin soas to function in a manner substantially similar to or substantiallyidentical to the cyclosporin, for example, cyclosporin A, in the presentmethods. Included, without limitation, within the useful cyclosporin Aderivatives are those selected from((R)-methylthio-Sar)³-(4′-hydroxy-MeLeu) cyclosporin A,((R)-(Cyclo)alkylthio-Sar)³-(4′-hydroxy-MeLeu)⁴-cyclosporin A, and((R)-(Cyclo)alkylthio-Sar)³-cyclosporin A derivatives described below.

These cyclosporin derivatives are represented by the following generalformulas (II), (III), and (IV) respectively:

swherein Me is methyl; Alk is 2-6C alkylene or 3-6C cycloalkylene; R isOH, COOH, alkoxycarbonyl, —NR₁R₂ or N(R₃)—(CH₂)—NR₁R₂; wherein R₁, R₂ isH, alkyl, 3-6C cycloalkyl, phenyl (optionally substituted by halo,alkoxy, alkoxycarbonyl, amino, alkylamino or dialkylamino), benzyl orsaturated or unsaturated heterocyclyl having 5 or 6 members and 1-3heteroatoms; or NR₁R₂ is a 5 or 6 membered heterocycle which may containa further N, O or S heteroatom and may be alkylated; R₃ is H or alkyland n is 2-4; and the alkyl moieties contain 1-4C.

In one embodiment, the cyclosporin component is effective as animmunosuppressant. Without wishing to be limited to any particulartheory of operation, it is believed that, in certain embodiments of thepresent invention, the cyclosporin component acts to enhance or restorelacrimal gland tearing in providing the desired therapeutic effect.

One important feature of the present invention is that the presentlyuseful compositions contain less than 0.1% by weight of the cyclosporincomponent. The advantages of such low-concentrations of cyclosporincomponents have been discussed in some detail elsewhere herein. Lowconcentrations of cyclosporin component, together with concentrations ofthe hydrophobic component such that the weight ratio of cyclosporincomponent to hydrophobic component is greater than 0.08, provides one ormore substantial advantages in the present methods.

Any suitable hydrophobic component may be employed in the presentinvention. Such hydrophobic component may be considered as comprising adiscontinuous phase in the presently useful cyclosporincomponent-containing emulsions, with the water or aqueous phase beingconsidered the continuous phase in such emulsion. The hydrophobiccomponent is preferably selected so as to solubilize the cyclosporincomponent, which is often substantially insoluble in the aqueous phase.Thus, with a suitable hydrophobic component included in the presentlyuseful emulsions, the cyclosporin component is preferably solubilized inthe emulsions.

In one very useful embodiment, the hydrophobic component comprises anoily material, in particular, a material which is substantially notmiscible in water. Examples of useful oily materials include, withoutlimitation, vegetable oils, animal oils, mineral oils, synthetic oils,and the like and mixtures thereof. Thus, the present hydrophiliccomponents may comprise naturally occurring oils, including, withoutlimitation refined naturally occurring oils, or naturally occurring oilswhich have been processed to alter their chemical structures to someextent or oils which are substantially entirely synthetic. One veryuseful hydrophobic component includes higher fatty acid glycerides.

Examples of useful hydrophobic components include, without limitation,olive oil, arachis oil, castor oil, mineral oil, silicone fluid and thelike and mixtures thereof. Higher fatty acid glycerides such as oliveoil, peanut oil, castor oil and the like and mixtures thereof areparticularly useful in the present invention. Excellent results areobtained using a hydrophobic component comprising castor oil. Withoutwishing to limit the invention to any particular theory of operation, itis believed that castor oil includes a relatively high concentration ofricinoleic acid which itself may be useful in benefiting ocular tissueand/or in providing one or more therapeutic effects when administered toan eye.

The hydrophobic component is preferably present in the presently usefulcyclosporin component-containing emulsion compositions in an amountgreater than about 0.625% by weight. For example, the hydrophobiccomponent may be present in an amount up to about 0.75% by weight orabout 1.0% by weight or about 1.5% by weight or more of the presentlyuseful emulsion compositions.

The presently useful compositions may include one or more othercomponents in amounts effective to facilitate the usefulness andeffectiveness of the present methods and/or the presently usefulcompositions. Examples of such other components include, withoutlimitation, emulsifier components, surfactant components, tonicitycomponents, poly electrolyte components, emulsion stability components,viscosity inducing components, demulcent components, acid and/or basesto adjust the pH of the composition, buffer components, preservativecomponents and the like.

In one very useful embodiment, the presently useful compositions aresubstantially free of preservatives. Thus, the presently usefulcompositions may be sterilized and maintained in a sterile conditionprior to use, for example, provided in a sealed package or otherwisemaintained in a substantially sterile condition.

Any suitable emulsifier component may be employed in the presentlyuseful compositions, provided, that such emulsifier component iseffective in forming maintaining the emulsion and/or in the hydrophobiccomponent in emulsion, while having no significant or undue detrimentaleffect or effects on the compositions during storage or use.

In addition, the presently useful compositions, as well as each of thecomponents of the present compositions in the concentration present inthe composition advantageously are ophthalmically acceptable.

Useful emulsifier components may be selected from such component whichare conventionally used and well known in the art. Examples of suchemulsifier components include, without limitation, surface activecomponents or surfactant components which may be anionic, cationic,nonionic or amphorteric in nature. In general, the emulsifier componentincludes a hydrophobic constituent and a hydrophilic constituent.Advantageously, the emulsifier component is water soluble in thepresently useful compositions. Preferably, the emulsifier component isnonionic. Specific examples of suitable emulsifier components include,without limitation, polysorbate 80, polyoxyalkylene alkylene ethers,polyalkylene oxide ethers of alkyl alcohols, polyalkylene oxide ethersof alkylphenols, other emulsifiers/surfactants, preferably nonionicemulsifiers/surfactants, useful in ophthalmic compositions, and the likeand mixtures thereof.

The emulsifier component is present in an amount effective in formingthe present emulsion and/or in maintaining the hydrophobic component inemulsion with the water or aqueous component. In one preferredembodiment, the emulsifier component is present in an amount in a rangeof about 0.1% to about 5%, more preferably about 0.2% to about 2% andstill more preferably about 0.5% to about 1.5% by weight of thepresently useful compositions.

Polyelectrolyte or emulsion stabilizing components may be included inthe presently useful compositions. Such components are believed to beeffective in maintaining the electrolyte balance in the presently usefulemulsions, thereby stabilizing the emulsions and preventing theemulsions from breaking down prior to use. In one embodiment, thepresently useful compositions include a polyanionic component effectiveas an emulsion stabilizing component. Examples of suitable polyanioniccomponents useful in the presently useful compositions include, withoutlimitation, anionic cellulose derivatives, anionic acrylicacid-containing polymers, anionic methacrylic acid-containing polymers,anionic amino acid-containing polymers and the like and mixturesthereof.

A particularly useful class of polyanionic components include one ormore polymeric materials having multiple anionic charges. Examplesinclude, but are not limited to:

-   -   metal carboxy methylcelluloses    -   metal carboxy methylhydroxyethylcelluloses    -   metal carboxy methylstarchs    -   metal carboxy methylhydroxyethylstarchs    -   hydrolyzed polyacrylamides and polyacrylonitriles    -   heparin    -   gucoaminoglycans    -   hyaluronic acid    -   chondroitin sulfate    -   dermatan sulfate    -   peptides and polypeptides    -   alginic acid    -   metal alginates    -   homopolymers and copolymers of one or more of:        -   acrylic and methacrylic acids        -   metal acrylates and methacrylates        -   vinylsulfonic acid        -   metal vinylsulfonate        -   amino acids, such as aspartic acid, glutamic acid and the            like        -   metal salts of amino acids        -   p-styrenesulfonic acid        -   metal p-styrenesulfonate        -   2-methacryloyloxyethylsulfonic acids        -   metal 2-methacryloyloxethylsulfonates        -   3-methacryloyloxy-2-hydroxypropylsulonic acids        -   metal 3-methacryloyloxy-2-hydroxypropylsulfonates        -   2-acrylamido-2-methylpropanesulfonic acids        -   metal 2-acrylamido-2-methylpropanesulfonates allylsulfonic            acid        -   metal allylsulfonate and the like.

One particularly useful emulsion stabilizing component includescrosslinked polyacrylates, such as carbomers and Pemulen® materials.Pemulen® is a registered trademark of B.F. Goodrich for polymericemulsifiers and are commercially available from B.F. Goodrich Company,Specialty Polymers & Chemicals Division, Cleveland, Ohio. Pemulen®materials include acrylate/C10-30 alkyl acrylate cross-polymers, or highmolecular weight co-polymers of acrylic acid and a long chain alkylmethacrylate cross-linked with allyl ethers of pentaerythritol.

The presently useful polyanionic components may also be used to providea suitable viscosity to the presently useful compositions. Thus, thepolyanionic components may be useful in stabilizing the presently usefulemulsions and in providing a suitable degree of viscosity to thepresently useful compositions.

The polyelectrolyte or emulsion stabilizing component advantageously ispresent in an amount effective to at least assist in stabilizing thecyclosporin component-containing emulsion. For example, thepolyelectrolyte/emulsion stabilizing component may be present in anamount in a range of about 0.01% by weight or less to about 1% by weightor more, preferably about 0.02% by weight to about 0.5% by weight, ofthe composition.

Any suitable tonicity component may be employed in accordance with thepresent invention. Preferably, such tonicity component is non-ionic, forexample, in order to avoid interfering with the other components in thepresently useful emulsions and to facilitate maintaining the stabilityof the emulsion prior to use. Useful tonicity agents include, withoutlimitation, glycerine, mannitol, sorbitol and the like and mixturesthereof. The presently useful emulsions are preferably within the rangeof plus or minus about 20% or about 10% from being isotonic.

Ophthalmic demulcent components may be included in effective amounts inthe presently useful compositions.

For example, ophthalmic demulcent components such ascarboxymethylcellulose, other cellulose polymers, dextran 70, gelatin,glycerine, polyethylene glycols (e.g., PEG 300 and PEG 400), polysorbate80, propylene glycol, polyvinyl alcohol, povidone and the like andmixtures thereof, may be used in the present ophthalmic compositions,for example, compositions useful for treating dry eye.

The demulcent components are preferably present in the compositions, forexample, in the form of eye drops, in an amount effective in enhancingthe lubricity of the presently useful compositions. The amount ofdemulcent component in the present compositions may be in a range of atleast about 0.01% or about 0.02% to about 0.5% or about 1.0% by weightof the composition.

Many of the presently useful polyelectrolyte/emulsion stabilizingcomponents may also be effective as demulcent components, and viceversa. The emulsifier/surfactant components may also be effective asdemulcent components and vice versa.

The pH of the emulsions can be adjusted in a conventional manner usingsodium hydroxide and/or hydrochloric acid to a physiological pH level.The pH of the presently useful emulsions preferably is in the range ofabout 6 to about 10, more preferably about 7.0 to about 8.0 and stillmore preferably about 7.2 to about 7.6.

Although buffer components are not required in the presently usefulcompositions, suitable buffer components, for example, and withoutlimitation, phosphates, citrates, acetates, borates and the like andmixtures thereof, may be employed to maintain a suitable pH in thepresently useful compositions.

The presently useful compositions may include an effective amount of apreservative component. Any suitable preservative or combination ofpreservatives may be employed. Examples of suitable preservativesinclude, without limitation, benzalkonium chloride, methyl and ethylparabens, hexetidine, phenyl mercuric salts and the like and mixturesthereof. The amounts of preservative components included in the presentcompositions are such to be effective in preserving the compositions andcan vary based on the specific preservative component employed, thespecific composition involved, the specific application involved, andthe like factors. Preservative concentrations often are in the range ofabout 0.00001% to about 0.05% or about 0.1% (w/v) of the composition,although other concentrations of certain preservatives may be employed.

Very useful examples of preservative components in the present inventioninclude, but are not limited to, chlorite components. Specific examplesof chlorite components useful as preservatives in accordance with thepresent invention include stabilized chlorine dioxide (SCD), metalchlorites such as alkali metal and alkaline earth metal chlorites, andthe like and mixtures thereof. Technical grade (or USP grade) sodiumchlorite is a very useful preservative component. The exact chemicalcomposition of many chlorite components, for example, SCD, is notcompletely understood. The manufacture or production of certain chloritecomponents is described in McNicholas U.S. Pat. No. 3,278,447, which isincorporated in its entirety by reference herein. Specific examples ofuseful SCD products include that sold under the trademark Dura Klor byRio Linda Chemical Company, Inc., and that sold under the trademarkAnthium Dioxide® by International Dioxide, Inc. An especially useful SCDis a product sold under the trademark Bio-Cide® by Bio-CideInternational, Inc., as well as a product identified by Allergan, Inc.by the trademark Purite®.

Other useful preservatives include antimicrobial peptides. Among theantimicrobial peptides which may be employed include, withoutlimitation, defensins, peptides related to defensins, cecropins,peptides related to cecropins, magainins and peptides related tomagainins and other amino acid polymers with antibacterial, antifungaland/or antiviral activities. Mixtures of antimicrobial peptides ormixtures of antimicrobial peptides with other preservatives are alsoincluded within the scope of the present invention.

The compositions of the present invention may include viscositymodifying agents or components, such as cellulose polymers, includinghydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC),ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, methyl celluloseand carboxymethyl cellulose; carbomers (e.g. carbopol, and the like);polyvinyl alcohol; polyvinyl pyrrolidone; alginates; carrageenans; andguar, karaya, agarose, locust bean, tragacanth and xanthan gums. Suchviscosity modifying components are employed, if at all, in an amounteffective to provide a desired viscosity to the present compositions.The concentration of such viscosity modifiers will typically varybetween about 0.01 to about 5% w/v of the total composition, althoughother concentrations of certain viscosity modifying components may beemployed.

The presently useful compositions may be produced using conventional andwell known methods useful in producing ophthalmic products includingoil-in-water emulsions.

In one example, the oily phase of the emulsion can be combined with thecyclosporin component to solubilize the cyclosporin component in theoily material phase. The oily phase and the water may be separatelyheated to an appropriate temperature. This temperature may be the samein both cases, generally a few degrees to about 10° C. above the meltingtemperature of the ingredient(s) having the highest melting point in thecase of a solid or semi-solid oily phase for emulsifier components inthe oily phase. Where the oily phase is a liquid at room temperature, asuitable temperature for preparation of a composition may be determinedby routine experimentation in which the melting point of the ingredientsaside from the oily phase is determined. In cases where all componentsof either the oily phase or the water phase are soluble at roomtemperature, no heating may be necessary. Non-emulsifying agents whichare water soluble are dissolved in the water and oil soluble componentsincluding the surfactant components are dissolved in the oily phase.

To create an oil-in-water emulsion, the final oil phase is gently mixedinto either an intermediate, preferably de-ionized water, phase or intothe final water phase to create a suitable dispersion and the product isallowed to cool with or without stirring. In the case where the finaloil phase is first gently mixed into an intermediate water phase, theresulting emulsion concentrate is thereafter mixed in the appropriateratio with the final aqueous phase. In such cases, the emulsionconcentrate and the final aqueous phase may not be at the sametemperature or heated above room temperature, as the emulsion may bealready formed at this point.

The oil-in-water emulsions of the present invention can be sterilizedafter preparation using heat, for example, autoclave steam sterilizationor can be sterile filtered using, for example, a 0.22 micron sterilefilter. Sterilization employing a sterilization filter can be used whenthe emulsion droplet (or globule or particle) size and characteristicsallows this. The droplet size distribution of the emulsion need not beentirely below the particle size cutoff of the 0.22 micron sterilefiltration membrane to be sterile-filtratable. In cases wherein thedroplet size distribution of the emulsion is above the particle sizecutoff of the 0.22 micron sterile filtration membrane, the emulsionneeds to be able to deform or change while passing through thefiltration membrane and then reform after passing through. This propertyis easily determined by routine testing of emulsion droplet sizedistributions and percent of total oil in the compositions before andafter filtration. Alternatively, a loss of a small amount of largerdroplet sized material may be acceptable.

The present oil-in-water emulsions preferably are thermodynamicalystable, much like microemulsions, and yet may not be isotropictransparent compositions as are microemulsions. The emulsions of thepresent invention advantageously have a shelf life exceeding one year atroom temperature.

The following non-limiting examples illustrate certain aspects of thepresent invention.

Example 1

Two compositions are selected for testing. These compositions areproduced in accordance with well known

Composition I Composition II wt % wt % Cyclosporin A 0.1  0.05 CastorOil 1.25 1.25 Polysorbate 80 1.00 1.00 Premulen ® 0.05 0.05 Glycerine2.20 2.20 Sodium hydroxide qs qs Purified Water qs qs pH 7.2-7.6 7.2-7.6Weight Ratio of Cyclosporin 0.08 0.04 A to Castor Oil

These compositions are employed in a Phase 3, double-masked, randomized,parallel group study for the treatment of dry eye disease.

The results of this study indicate that Composition II, in accordancewith the present invention, which has a reduced concentration ofcyclosporin A and a cyclosporin A to castor oil ratio of less than 0.08,provides overall efficacy in treating dry eye disease substantiallyequal to that of Composition I. This is surprising for a number ofreasons. For example, the reduced concentration of cyclosporin A inComposition II would have been expected to result in reduced overallefficacy in treating dry eye disease. Also, the large amount of castoroil relative to the amount of cyclosporin A in Composition II might havebeen expected to cause increased eye irritation relative to CompositionI. However, both Composition I and Composition II are found to besubstantially non-irritating in use.

Using relatively increased amounts of castor oil, with reduced amountsof cyclosporin component, as in Composition II, is believed to takeadvantage of the benefits, for example the ocular lubrication benefits,of castor oil, as well as the presence of ricinoleic acid in the castoroil, to at least assist in treating dry eye syndrome in combination withcyclosporin A.

In addition, it is found that the high concentration of castor oilrelative to cyclosporin component, as in Composition II, provides theadvantage of more quickly or rapidly (for example, relative to acomposition which includes only 50% as much castor oil) breaking down orresolving the emulsion in the eye, for example, as measured bysplit-lamp techniques to monitor the composition in the eye for phaseseparation. Such rapid break down of the emulsion in the eye reducesvision distortion as the result of the presence of the emulsion in theeye, as well as facilitating the therapeutic effectiveness of thecomposition in treating dry eye disease.

Using reduced amounts of cyclosporin A, as in Composition II, to achievetherapeutic effectiveness mitigates even further against undesirableside effects and potential drug interactions. Prescribing physicians canprovide (prescribe) Composition II to more patients and/or with fewerrestrictions and/or with reduced risk of the occurrence of adverseevents, e.g., side effects, drug interactions and the like, relative toproviding Composition I.

While this invention has been described with respect to various specificexamples and embodiments, it is to be understood that the invention isnot limited thereto and that it can be variously practiced within thescope of the following claims.

1.-36. (canceled)
 37. A method of treating dry eye disease, the methodcomprising topically administering to the eye of the human an emulsionat a frequency of twice a day, wherein the emulsion comprisescyclosporin A in an amount of about 0.05% by weight, polysorbate 80,Pemulen, water, and castor oil in an amount of about 1.25% by weight;and wherein the topical ophthalmic emulsion is effective in treating dryeye disease.
 38. The method of claim 37, wherein the emulsion furthercomprises a tonicity agent or a demulcent component.
 39. The method ofclaim 38, wherein the tonicity agent or the demulcent component isglycerine.
 40. The method of claim 37, wherein the emulsion furthercomprises a buffer.
 41. The method of claim 40, wherein the buffer issodium hydroxide.
 42. The method of claim 37, wherein the topicalophthalmic emulsion further comprises glycerine and a buffer.
 43. Themethod of claim 37, wherein the emulsion comprises polysorbate 80 in anamount of about 1.0% by weight.
 44. The method of claim 37, wherein theemulsion comprises Pemulen in an amount of about 0.05% by weight. 45.The method of claim 37, wherein the emulsion further comprises glycerinein an amount of about 2.2% by weight and a buffer.
 46. The method ofclaim 45, wherein the buffer is sodium hydroxide.
 47. The method ofclaim 37, wherein, when the emulsion is administered to an eye of ahuman in an effective amount in treating dry eye syndrome, the blood ofthe human has substantially no detectable concentration of cyclosporinA.
 48. The method of claim 42, wherein the emulsion has a pH in therange of about 7.2 to about 7.6.
 49. The method of claim 37, wherein theemulsion is as substantially therapeutically effective as an emulsioncomprising cyclosporin A in an amount of 0.1% by weight and castor oilin an amount of 1.25% by weight.
 50. The method of claim 37, wherein theemulsion achieves at least as much therapeutic effectiveness as anemulsion comprising cyclosporin A in an amount of 0.1% by weight andcastor oil in an amount of 1.25% by weight.
 51. The method of claim 37,wherein the emulsion breaks down more quickly in the eye of a human,once administered to the eye of the human, thereby reducing visiondistortion in the eye of the human as compared to an emulsion thatcontains only 50% as much castor oil.
 52. The method of claim 37,wherein the emulsion, when administered to the eye of a human,demonstrates a reduction in adverse events in the human, relative to anemulsion comprising cyclosporin A in an amount of 0.1% by weight andcastor oil in an amount of 1.25% by weight.
 53. The method of claim 52,wherein the adverse events include side effects.
 54. A method ofreducing side effects in a human suffering from dry eye syndrome, themethod comprising the step of topically administering to the eye of thehuman an emulsion at a frequency of twice a day, wherein the emulsioncomprises: cyclosporin A in an amount of about 0.05% by weight; castoroil in an amount of about 1.25% by weight; polysorbate 80 in an amountof about 1.0% by weight; Pemulen in an amount of about 0.05% by weight;a tonicity component or a demulcent component in an amount of about 2.2%by weight; a buffer; and water.
 55. The method of claim 54, wherein thebuffer is sodium hydroxide.
 56. The method of claim 54, wherein thetonicity component or the demulcent component is glycerine.
 57. Themethod of claim 54, wherein, when the emulsion is administered to theeye of a human in an effective amount in treating dry eye syndrome, theblood of the human has substantially no detectable concentration of thecyclosporin A.
 58. The method of claim 54, wherein the emulsion has a pHin the range of about 7.2 to about 7.6.
 59. The method of claim 54,wherein the emulsion is effective in treating dry eye disease.
 60. Amethod of treating dry eye disease, the method comprising the step oftopically administering to an eye of a human an emulsion, the emulsioncomprising: cyclosporin A in an amount of about 0.05% by weight; castoroil in an amount of about 1.25% by weight; polysorbate 80 in an amountof about 1.0% by weight; Pemulen in an amount of about 0.05% by weight;glycerine in an amount of about 2.2% by weight; sodium hydroxide; andwater, wherein the emulsion is effective in treating dry eye disease.61. The method of claim 60, wherein the emulsion has a pH in the rangeof about 7.2 to about 7.6.